Genes mapping in the H-2K/D and I regions of the major histocompatibility complex (H-2) of mice play a pivotal role in regulating the interactions of lymphocytes in the immune response. The linkage of H-2K/D and I region analogs has been maintained throughout mammalian evolution suggesting that H-2K/D and I region genes interact to regulate immune responses which are selectively advantageous. I have observed that the T cell response to single non-H-2 histocompatibility (H) alloantigens is regulated by antigen-specific immune response (IR) genes mapping in both I and H-2K/D regions. I propose to conduct a comprehensive genetic and immunological analysis of the functional interactions of these two Ir gene systems. The Ir genes which control recipient responsiveness in vivo and in vitro will be characterized by determining their H antigen specificity, minimum number, and intra-H-2 map positions. Similarly, the Ir genes which regulate the presentation or immunogenicity of non-H-2 antigens will be mapped and their H antigen-specificity determined. The possible preferential association of single H antigen-specific fast responsiveness and high immunogenicity alleles at I and H-2K/D loci in specific H-2 haplotypes will be investigated; this investigation is aimed at revealing I:H-2K/D linkage disequilibrium in mice. The cellular level of expression of the genes controlling recipient responsiveness will be determined by Ly phenotyping T cells responding to non-H-2 H antigens. Similarly, the identity of cells presenting non-H-2 H antigens will be determined. The suspected role of I and H-2K/D Ir genes in antigen-specific regulation of the interactions between non-H-2 H antigen-specific T cells and H antigen-positive stimulator and target cells will be confirmed. Techniques will be employed to demostrate that non-H-2 H antigens associated with Ir gene products, which have variable affinity for H antigens, to form immunogenic complexes on the cell membrane. Complementary experiments will be conducted to determine the specificity of the T cell receptor(s) for non-H-2 antigen and "self" H-2 complex molecules by serological characterization of the respective T cell receptor idiotypes.